Baicalin (BG) is one of the major components of Sho-Saiko-To. We found a new substance as the metabolite of BG in human plasma after oral administration of Sho-Saiko-To. The metabolite was identified as baicalein 6-O-sulfate (BS) by comparing its retention time in HPLC and electrospray ionization mass spectra (ESI-MS)/MS methods with that of an authentic sample. Time profiles for the plasma concentrations of BS and BG after oral administration of Sho-Saiko-To (EK-9) at a daily dose (6g), were investigated in 14 healthy male volunteers. The determination for the concentrations of BS and BG in human plasma was developed by the HPLC method using electrochemical detector (ECD). Each 1 ml of the plasma specimen was used for the solid phase extraction. The calibration curves of BS and BG showed a good linearity between 5 and 300 ng/ml. The quantitative limits of BS and BG in human plasma were 5ng/ml. Using this method, BS was detected after 1 h, reached a maximum level at 5 h and then decreased to the level less than the quantitative limit after 36 h, and the plasma level of BS showed a slight peak at 24 h. BG was detected after 1 h, reached a maximum level at 5 h and then decreased to the level less than the quantitative limit after 36 h, and the plasma level of BG showed two peaks at 12 h and 24 h.
A series of the aryl-substituted N'-2-(2-hydroxy-2-phenyl) ethyl derivatives of N"-methanesulfonyl-N-2-((5-dimethylaminomethyl or 5-methylaminomethyl)furfurylthio)ethylguanidine have been synthesized as potential antisecretory and mucosal protective antiulcer agents. The synthetic routes involves, at the last stage, the reaction of 2-hydroxy-2-phenylethylamines with N-2-(furfurylthio)-ethyl-N'-methanesulfonyl-S-methylisothiourea or its O-phenylisourea counterpart. The primary screening test to assess the inhibitory activity of the synthetic compounds on histamine-induced gastric acid secretion was carried out in anesthetized rats by the lumen-perfusion technique of Ghosh and Schild and also by the pylorus-ligated preparation method. The best profile of histamine H2-antagonist activity was much better than that of the prototype ranitidine, and obtained with N'-(2-(2-hydroxy-2-(4-hydroxyphenyl))ethyl-N"-methanesulfonyl-N-2-(5-(methylaminomethyl)furfurylthio)ethylguanidine (12f), which was also characterized by enhancing the gastric mucosal blood flow in rabbits as observed by the thermoelectric method. This compound 12f, designated as T-593, significantly inhibited the formation of the indomethacin-induced gastric lesions in rats ; 3.5-fold more potent than ranitidine, but 4-fold less active than famotidine. On the other hand, T-593 and famotidine displayed comparable activities in healing the acetic acid-induced gastric ulcer with and without the dosing of indomethacin. Additional notable features of T-593, as determined in rats, are that its protective effect on the hemorrhagic shock-induced lesion under the prior dosing of histamine is ca. 10-and 2-fold greater than ranitidine and famotidine, respectively, and that a decrease in the gastric mucosal blood flow caused by a partial blood-withdrawal is more strongly recovered with T-593 than with famotidine. These experimental results suggest that the antiulcer efficacy of T-593 can be explained by its dual activities : antisecretion of gastric acid and, more importantly, protection of gastric mucous membrane.
Diels-Alder reactions of 1-unsubstituted 2 (1H)-pyridones having two electron-withdrawing groups on the ring with a diene were carried out and the reactions gave expected Diels-Alder adducts. The yields of adducts were well correlated with the corresponding stabilization energies (ΔE) between a diene and dienophiles calculated using the semiempirical molecular orbital method.